Neurotropic Gamma-Delta T-Cell Lymphoma With CD30-Positive Lymphoid Infiltrates.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a clonal proliferation of gamma-delta T cells with a cytotoxic phenotype that is typically characterized by an aggressive clinical course with ulcerative plaques or subcutaneous nodules. In this report, the authors describe a patient who developed an ulcerated tumor on the left upper extremity and painful papules and nodules on the right lower extremity. Interestingly, several of the papulonodules on the right lower extremity underwent spontaneous involution. A skin biopsy of the papulonodular lesion demonstrated a superficial and deep perivascular interstitial infiltrate with a population of pleomorphic enlarged CD30-positive T cells. These enlarged lymphocytes lacked expression of TCR beta, CD4, CD8, and the pan T-cell antigen CD7, but were positive for TCR gamma, supporting the diagnosis of PCGD-TCL. The patient rapidly developed pain and severe weakness in the left upper limb and MRI revealed extensive neurolymphomatosis of the left brachial plexus. The patient was treated with chemotherapy with complete remission achieved. Unfortunately, her response was transient and the patient relapsed and ultimately died due to her disease. In this article, the authors describe an extraordinary case of a CD30-positive PCGD-TCL to expand the histopathological spectrum of CD30-positive and gamma-delta-positive lymphoproliferative disorders.

Myeloid Cell Nuclear Differentiation Antigen (MNDA) Expression Distinguishes Extramedullary Presentations of Myeloid Leukemia From Blastic Plasmacytoid Dendritic Cell Neoplasm.

Myeloid neoplasms constitute one of the most common malignancies in adults. In most cases these proliferations initially manifest in the blood and marrow; however, extramedullary involvement may precede blood or marrow involvement in a subset of cases, making a definitive diagnosis challenging by morphologic and immunohistochemical assessment alone. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive entity that frequently presents in extramedullary sites and can show morphologic and immunophenotypic overlap with myeloid neoplasms. Given that BPDCN and myeloid neoplasms may both initially present in extramedullary sites and that novel targeted therapies may be developed that exploit the unique molecular signature of BPDCN, new immunophenotypic markers that can reliably separate myeloid neoplasms from BPDCN are desirable. We evaluated the utility of myeloid cell nuclear differentiation antigen (MNDA) expression in a series of extramedullary myeloid leukemias (EMLs) and BPDCN. Forty biopsies containing EML and 19 biopsies containing BPDCN were studied by MNDA immunohistochemistry. The majority of myeloid neoplasms showed nuclear expression of MNDA (65%). In contrast, all cases of BPDCN lacked MNDA expression. These findings show that MNDA is expressed in the majority of EMLs and support the inclusion of MNDA immunohistochemistry in the diagnostic evaluation of blastic hematopoietic infiltrates, particularly when the differential diagnosis is between myeloid leukemia and BPDCN.

Intravascular crystal deposition: an early clue to the diagnosis of type 1 cryoglobulinemic vasculitis.

Cutaneous small vessel vasculitis (CSVV) is a nonspecific finding with an extensive differential diagnosis. It is critically important to distinguish skin-limited presentations of CSVV from severe life-threatening systemic vasculitides presenting with CSVV as an initial manifestation. It can be challenging to determine which patients presenting with CSVV are at risk for systemic disease. Standard histopathologic evaluation, direct immunofluorescence, and serologic evaluation is typically required to exclude a systemic vasculitis. Type 1 cryoglobulinemia may rarely present with CSVV. Herein, we report a case of type 1 cryoglobulinemia in the setting of occult multiple myeloma. CSVV with prominent intravascular crystal formation was noted. The presence of intravascular crystals in the setting of CSVV may represent an important early clue to the diagnosis of type 1 cryoglobulinemic vasculitis.

Striated muscle hamartoma presenting as a chin cyst in a newborn.

Striated muscle hamartoma is a rare, benign mesenchymal neoplasm that typically arises in the midline of a newborn patient. We report a clinically and histopathologically classic case of striated muscle hamartoma presenting as a chin cyst in a newborn female.

CD8(+) granulomatous cutaneous T-cell lymphoma: a potential association with immunodeficiency.

BACKGROUND: Granulomatous cutaneous T-cell lymphoma (G-CTCL) is a rarely encountered entity. Most G-CTCL is CD4(+), with granulomatous mycosis fungoides representing the vast majority of cases. Because of the rarity of CD8(+) G-CTCL, there is a paucity of data regarding the clinicopathologic features and expected course. OBJECTIVE: To describe the clinical and histopathologic features of G-CTCL. METHODS: This is a retrospective review of collected cases. RESULTS: We present 4 cases of CD8(+) G-CTCL. Patients presented with papules and nodules on the trunk and extremities without antecedent patch or plaque disease. In all cases, biopsy specimens were obtained, and these revealed a dense granulomatous infiltrate accompanied by an atypical lymphoid infiltrate of CD8(+) T cells. T-cell clonality studies were positive in 3 of 4 cases. Staging was negative for nodal involvement, but lung granulomas were seen in all cases. In all 4 cases, the patient's medical history was significant for immunodeficiency, either primary or iatrogenic. All 4 patients had slowly progressive disease. LIMITATIONS: This is a small retrospective case series. CONCLUSIONS: CD8(+) G-CTCL appears to be associated with immunodeficiency. The finding of a CD8(+) G-CTCL should prompt an evaluation for underlying immunodeficiency. Additional studies are required to validate these conclusions.

Clumped perinuclear BAP1 expression is a frequent finding in sporadic epithelioid Spitz tumors.

BACKGROUND: BRCA1-associated protein 1 (BAP1) represents a recently identified tumor suppressor protein. Loss of BAP1 has been observed in cutaneous epithelioid Spitz tumors. These cutaneous melanocytic tumors show a distinct histopathologic phenotype characterized by an intradermal sheet-like proliferation of epithelioid melanocytes. METHODS: We retrospectively reviewed the clinical outcomes, histopathologic findings and immunophenotype in spitzoid melanocytic neoplasms with the morphologic features seen in BAP1 mutated Spitz tumors. Cases were obtained from our files. BAP1 immunohistochemistry was evaluated dichotomously for the presence of nuclear staining. RESULTS: Fifteen of 19 cases showed loss of nuclear BAP1 expression. Of the 15 cases displaying nuclear loss of BAP1, clumped perinuclear staining was observed in 8 cases while 7 cases showed complete loss. Follow up ranging from 0-45 months (mean 17 months) was uneventful. CONCLUSIONS: Our data are consistent with an indolent overall clinical course for epithelioid Spitz tumors with loss of BAP1. Furthermore, a large subset of epithelioid Spitz tumors display loss of nuclear expression but show a reproducible clumped perinuclear staining pattern.

Intertriginous mycosis fungoides: a distinct presentation of cutaneous T-cell lymphoma that may be caused by malignant follicular helper T cells.

BACKGROUND: Follicular helper T cells are a subset of helper T cells that facilitate B-cell recruitment and maturation. Rare cases of cutaneous T-cell lymphoma manifesting as de novo tumor lesions in intertriginous skin contain an infiltrate rich in B cells. These cases may represent malignant counterparts of skin-homing follicular helper T cells. OBSERVATIONS: Two men and 1 woman (age range, 35-58 years) were seen with predominantly intertriginous tumor-stage cutaneous T-cell lymphoma lesions characterized by the absence of epidermotropism and the presence of a mixed infiltrate rich in B cells. Two of the patients died of the disease less than 3 years from the initial diagnosis. The surviving patient has aggressive disease and underwent hematopoietic stem cell transplantation. Two of the patients had a prominent CXCL13+, Bcl6/CD3+, and programmed death protein 1-positive follicular helper T-cell population. CONCLUSIONS: The intertriginous tumor variant of cutaneous T-cell lymphoma is heterogeneous but may be associated in some cases with a follicular helper T-cell immunophenotype. These patients may follow an aggressive clinical course. Tumor progression in sanctuary sites on patients receiving phototherapy may manifest as a similar clinical phenotype. Further characterization of the disease process is needed to confirm this observation.

Homogeneous staining regions for cyclin D1, a marker of poor prognosis in malignant melanoma.

Homogeneous staining regions (HSRs) have been previously shown to confer a worse prognosis in solid tumors and myelodysplastic syndromes. We previously reported a single case of melanoma with HSR for cyclin D1 and postulated that HSR for cyclin D1 is an independent poor prognostic indicator. Herein, we report 7 cases of melanoma with HSR for cyclin D1. The cases occurred in elderly men and women with an average age of 65 years. Three cases occurred in areas of intermittent sun exposure, 2 cases occurred in chronically sun-damaged areas, and 2 cases were acral. HSR correlated with aggressive histology. The average Breslow depth was 2.7 mm (range, 1-11 mm), the average mitotic index was 5.1 per square millimeter, and 5 of the 7 cases were ulcerated. Clinical follow-up was available for 6 of the 7 cases. Five of the 6 cases for which clinical follow-up was available metastasized, and 1 patient died of metastatic melanoma. Three cases with metastatic disease occurred in primary melanomas with lower Breslow depths, ranging from 1.0 to 1.4 mm. These additional cases of melanoma with an aggressive clinical course provide further evidence of the prognostic significance of HSR for cyclin D1 in melanoma. Larger cohort studies are needed to validate this observation.

Enhanced detection of spitzoid melanomas using fluorescence in situ hybridization with 9p21 as an adjunctive probe.

The use of molecular diagnostic methods such as fluorescence in situ hybridization (FISH) for challenging melanocytic neoplasms is becoming more widespread. In light of the diagnostic difficulty they pose, spitzoid melanocytic neoplasms constitute an area of greatest potential utilization. In this study we wished to evaluate the sensitivity of the currently used melanoma FISH probe assay in a group of unambiguous spitzoid melanomas. On the basis of comparative genomic hybridization data, copy number losses at chromosome 9 have long been recognized as a frequent event in melanoma. In this study we wished to evaluate the efficacy of 9p21 as a potential FISH target and then evaluate the added benefit of reflexing the standard melanoma FISH assay, with FISH targeting 9p21 and the centromere of chromosome 9 (Cep9). Cep9 was included as a control to exclude inadequate hybridization or truncation as a source of homozygous deletions. We first studied a training set of 85 melanomas and 58 nevi with FISH targeting 9p21 and Cep9. As per previous methodology, 30 cells were enumerated. In the training set, the nevi had a mean number of cells with homozygous 9p21 loss of 0.97, with a standard deviation of 1.26. The melanomas had a mean of 7.1 and a standard deviation of 6.76. This difference was significant (P=2×10(-12)). On the basis of the training set, we identified a cutoff of 10 homozygous deletions to distinguish between melanoma and nevi. In a subsequent validation set consisting of 76 melanomas and 88 nevi, we found this cutoff to have a sensitivity of 33% and a specificity of 100%. Finally, in our group of 43 unequivocal spitzoid melanomas, standard FISH against chromosomes 6 and 11 was 70% sensitive. Homozygous 9p21 loss was present in 11 of 27 (41%) cases tested. By combining the standard melanoma FISH assay with the 9p21 FISH assay, a combined sensitivity of 85% was found. Among these 27 cases tested with 9p21, there were 7 cases that were negative by the standard melanoma FISH assay but that were positive by 9p21, suggesting that the 9p21 assay may be highly complementary to the standard melanoma FISH assay. Hence, in this study, we validated the efficacy of 9p21/Cep9 as a diagnostic FISH assay in melanoma, and demonstrated its complementary effect to the standard FISH assay. 9p21 may be particularly helpful in lesions with spitzoid morphology.

Resource utilization and quality of life associated with congenital ichthyoses.

We explored resource utilization (ResUtil) and quality of life (QOL) associated with congenital ichthyoses (CI). Subjects completed an online survey related to clinical severity, demographics, ResUtil, and QOL as measured according to the Dermatology Life Quality Index (DLQI). Validated Likert scales were used to evaluate severity of hyperkeratosis, erythema, and alopecia. ResUtil was determined according to time spent daily treating CI symptoms (TimeTx) and number of ichthyosis-related dermatology visits (DermVisits) per year. We used linear regression to investigate predictors of a transformed DLQI (sqrtDLQI) and logistic regression for ResUtil. Of 235 subjects, 60.2% were female, 83.8% were Caucasian, 42.3% had a family history (FamHx) of CI, and the mean age was 28.7 years (SD 20.3). Predictors for worse QOL were hyperkeratosis severity (ß = 0.27, p < 0.01), erythema (ß = 0.27, p < 0.01), TimeTx (ß = 0.21, p < 0.01), ichthyosis type (ß = 0.09, p < 0.01), and age (ß = 0.01, p = 0.02). Predictors for DermVisits were hyperkeratosis severity (odds ratio [OR] = 1.38, 95% confidence limit [CL] = 1.01, 1.87), FamHx (OR = 0.28, 95% CL = 0.09, 0.85), age (OR = 0.97, 95% CI = 0.96, 0.99), and alopecia severity (OR = 1.43, 95% CL = 1.12, 1.82). Predictors for treatment duration were erythema (OR = 1.35, 95% CL = 1.02, 1.78), age (OR = 0.98, 95% CL = 0.96, 0.99), and DLQI (OR = 1.09, 95% CL = 1.03, 1.15). Increased hyperkeratosis severity and erythema negatively impact QOL in the CI. Furthermore, increased disease severity predicted greater ResUtil, whereas increased age and FamHx predicted less ResUtil. Our findings suggest that better therapies and increased patient education may improve QOL and decrease ResUtil.

Efficacy of mycophenolate mofetil in antimalarial-resistant cutaneous lupus erythematosus.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunomodulatory drug shown to be effective in the treatment of systemic lupus erythematosus. Several anecdotal reports have suggested that MMF may be efficacious in the treatment of cutaneous lupus erythematosus (CLE). OBJECTIVES: Our objective was to summarize and report our experience with the use of MMF in patients with CLE recalcitrant to antimalarial therapy. METHODS: We retrospectively analyzed our open-label observations of 24 patients with CLE refractory to antimalarial therapy. The records of all patients visiting the Rheumatic Skin Disease Clinic at the University of Texas Southwestern Medical Center at Dallas from January 1, 2001, to July 1, 2006, were reviewed. RESULTS: MMF was tolerated well and, in conjunction with other therapies, was highly effective in the treatment of antimalarial-resistant CLE. With the addition of MMF to the existing regimen, a majority of patients achieved full control of disease signs and symptoms. All patients experienced some degree of improvement. LIMITATIONS: This is an open-label retrospective review. Severity of disease was assessed by qualitative assessment of the clinician. MMF was not used as monotherapy. CONCLUSIONS: Our results indicate that MMF, used as an additional agent in conjunction with standard therapy, is both well tolerated and efficacious in the treatment of refractory CLE. Despite the obvious limitations of the study, we believe this represents further evidence that MMF should be considered early in the treatment of patients refractory to antimalarial therapy.

Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma.

BACKGROUND: Blue nevus-like melanomas are melanomas that arise in association with blue nevi or closely simulate the histopathologic appearance of a blue nevus, usually a cellular blue nevus (CBN). Although the majority of CBN can be readily distinguished from blue nevus-like melanoma by conventional microscopy, there are a subset of cases where this distinction may be exceedingly difficult or impossible. METHODS: In this study, we evaluated the ability of a fluorescence in situ hybridization (FISH) assay targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1) and the centromere of chromosome 6 (Cep6) to distinguish between CBN and blue nevus-like melanoma. We identified five cases of blue nevus-like melanoma and 12 cases of CBN. RESULTS: The FISH assay was performed with 100% sensitivity and 100% specificity. Three of five cases met the 6p25/Cep6 criteria, all five met the 6p25 gain criteria and three of five met the 6q23/Cep6 loss criteria. None of the cases met criteria for gains in 11q13. None of the 12 CBN met any criteria for melanoma. CONCLUSIONS: A combined analysis of clinical aspects, histopathologic changes and FISH analysis could potentially contribute significantly to the ability of pathologists to discriminate between blue nevus-like melanoma and blue nevi in challenging cases.

Vitamin D levels, dietary intake, and photoprotective behaviors among patients with skin cancer.

Photoprotection against ultraviolet light is an important part of our armamentarium against actinically derived skin cancers. However, there has been concern that adherence to photoprotection may lead to low vitamin D status, leading to negative effects on patients' health. In this work we discuss previous findings in this area, which do not give a clear picture as to the relationship between vitamin D levels and photoprotection measures, as well as research performed by the authors, who did not detect a relationship between serum 25(OH)D levels and adherence to photoprotection measures in subjects with skin cancer, as assessed by the use of sunscreen, clothing, hats, sunglasses, and umbrellas/shade through the Sun Protection Habits Index. Subjects who took vitamin D oral supplementation had greater serum 25(OH)D levels than those who did not, whereas dietary intake through foods did not predict 25(OH)D levels in the authors' study. However, there was a high prevalence of vitamin D insufficiency and deficiency in the authors' study population, highlighting the importance of assessing vitamin D status and recommending oral vitamin D supplementation when indicated.

Sarcomatoid renal cell carcinoma presenting in the oropharynx.

Metastasis stemming from a distant malignancy is far less common than an oropharyngeal primary and represents only 1% of all oral neoplasms. The difficulty in diagnosing a metastasis in the oropharynx may be compounded if the lesion is poorly differentiated and bears little resemblance to the primary tumor. We present the case of synchronous metastatic renal cell carcinoma of the mandibular gingiva in a woman with sarcomatoid clear cell renal cell carcinoma. The metastatic lesion was poorly differentiated and lacked expression of the renal cell carcinoma (RCC) antigen. In contrast, PAX-8 staining was strongly positive. This case serves to highlight the diagnostic difficulty posed by poorly differentiated lesions in the oropharynx and reinforces the sensitivity of the cell lineage-specific transcription factor PAX-8 in poorly differentiated RCC.

Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation.

Epidermodysplasia verruciformis is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus serotypes. Epidermodysplasia verruciformis is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present epidermodysplasia verruciformis in a father and a son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 or EVER2. Epidermodysplasia verruciformis in this father/son pair in a nonconsanguinous pedigree is consistent with autosomal dominant inheritance. This is the first report of autosomal dominant transmission of epidermodysplasia verruciformis, providing further evidence of the genetic heterogeneity of epidermodysplasia verruciformis.

A finding of granuloma faciale associated with basal cell carcinoma.

The clinical differential diagnosis of violaceous plaques on the face is broad and includes both neoplasms and inflammatory dermatoses. We report the first case of a basal cell carcinoma (BCC) superficial to an underlying granuloma faciale (GF). This is a single case report with clinicopathological correlation. Histological examination of a skin biopsy from the cheek revealed superficial BCC and GF. This case constitutes the first reported finding of coincident GF and BCC.